Document BMO9OXJJxXN627k9rzOJrkym

November- 28, 1947 Dr. C. R. Bickerton Blackburn, Bard Hall, Box 134, 50 Haven Avenue, New York City J2. Dear Dp. Blackburn: I am glad, indeed, to hear from you, having learned from the London office of Associated Ethyl Company Limited, and also from Dr. Fairley, of your being in this courtly. I had intended getting in touch with you, so that you might know that we shall be very pleased to have you visit us, and so as, also, to have an opportunity to discuss with you the cases referred to in your- caper. I had a rather complete report on these cases some Weeks ago, and I felt it necessary to write to the London office and to Dr. Fairley at once concerning them. Finding that you were to be here, I cannot but feel that it is important that we see you and present our views oh this subject. Whether you hear from Australia or not, promptly, I wish to assure you that-you are fully authorized to visit Cincinnati for the purpose of consulting with us on this and other problems which are of concern to Associated Fthyl. A number of the technical and medical representatives of the Company have been sent to this countiy and to Cincinnati at Company expense, for the purpose of an exchange of information, and it would be most unfortunate if you were not to do so if you can find the time during your stay. For our part, we shall welcome you and will under take to make your visit worth your while. Now as to the paper, I should prefer to leave its disposition until such a time as we can discuss the situation fully. I personally, believe, and have so expressed myself to Dr. Fairley, that your use of B.A.L. in these cases was without noteworthy effect upon the clinical outcome. The background of this opinion will require more evidence than I can put in a brief letter, but we have had occasion to study the effects of B.A.L. in a series of cases of lead, mercury, arsenic and other metallic poisoning, and we have also treated quite a number of cases of tetraethyl lead poisoning - not with B.A.L., but by other means i. The course of the cases described by yourself was in no wise unusual, nor was recovery in any way remarkable. Certain other aspects of the problem have changed somewhat with; the years . and on the basis of experience, and therefore we should be reluctant to sponsor the appearance of an article which might wbll result in controversy, and which would fail in some respects to present what is now known on this subject. I send you herewith one brief article, the only one we have published, to date, on B.A.L. It will serve to present only one aspect of our observations . Certainly it will show why the analytical findings in your cases may have been rendered somewhat erratic by the administration of B.A.L. We should be 4isposed to feel that one should go very slowly I'Dr. G. R. Bickerton Blackburn - (2) - November 28, 19^7 Indeed In recommending the use of B.A.L. in the therapy of tetraethyl lead poisoning. I am frank to say that I should entertain very serious reservations concerning its use, even experimentally, in any case o: tetraethyl lead poisoning if I had any considerable doubt as to the likelihood of the survival of the patient. Your experience leaves me somewhat less fearful on tnis score, but I still have some concern as :o the possible effects of its use. I shall retain your manuscript pntil I hear from you further, in the nope that we shall have an opportunity to go over it together in some detail. I sincerely trust that yopr stay in this country will be interesting and profitable, and that we shall have an opportunity to share some portion of it with you. Sincerely yours, Ail ef Robert A. Kehoe, M. D. HE 0020052 Dr G .11 .Bickerton Blackburn, Bard kail, Box 134 50 liaven Avenue, Lei:i York 32., Y.Y. 51 Lovsmber 47 . Dr. Robert 4. Rehoe, University of Cincinnati College of medicine, Cincinnati, Ghio. Dear Dr ICehoe, I an writing to you on the advice of Dr R.Loeb and Dr n.Gilnan of the College of Physicians and Surgeons, Columbia University, lie'." York, where I am at present. I have a Rockefeller foundation grant for about a year. I'enclose a draft paper on the treatment of DDL poisoning with DAL. I was fortunate enough to treat two men poisoned with DDL as I am the medical adviser to the Bthyl Company: in i7.3.",V., Australia, and both men recovered. At the time I treated tliestt issai I baa seen no reference to the efficacy, or otherwise, of 3AL in the treatment of lead poisoning but since then have - heard very conflicting .opinions.- It was difficult to avoid she conclusion that DAL had been effective in the treatment of at least one of my patients. I would appreciate your advice concerning the desirability of reporting these two cases and, if it is desirable to report then, to whom I should submit the report for publication. I tm aware that much more should have been done concerning the lead excretion studies and that the method of estimating the lead in the urine was probably quite inadequate circumstances precluded a fuller study. The 3thyl Company has asked me to visit:Cincinnati while I am over here and I propose to do this as soon as I can - probably in a few months time. So far the request has been verbal so I will wait for more definite instructions. I hope my request does not cause you too much inconvenience, yours sincerely, C R Bickerton Blackburn 0020053 N20106.01 .. ygm--3gBYL XS&D POISOHim TRRAgBD WITH BAL ( 2: VdiraercantoproTianol. British Anti-Lewisite . ) G. S. Bickerton Blackburn M*D. K.R.C.F"., M.R.A,C.P ; r ' > ' !S. N20106.02 , . TETIU-hTBYT, T.r.AD POISa: i?G British WITH BkL {2z^imrGmtovTor,nnol. r-H: . ,>;3 . v, C. B. Bickerton Blackburn M.B., M.B.G.P. , JhB. A.C.P. V Tetra-ethyl lead is a colourless and somewhat volatile liquid used as an ''anti-knock* in gasoline. It is-insoluble in water but miscible with fats in all proportions. In the presence of sunlight it say decompose to 1, 2. triethyl lead compounds which are water soluble, Motor and aviation fuels may contain up to 3 ml- of tetra-ethyl lead per gallon without their vapours being toxic to sanhor experimental animals, Poisoning, has most often been, reported, in men engaged in blend-jug gasoline or cleaning out storage tanks that have contained leaded gasoline for some time, ,absorption taking place either by, the respiratory tract or by the skin, through both of which tatra-ethyl lead easily passes. Storage tanks are especially dangerous for tetra-ethyl lead may be present in relatively large amounts in the "scale" on the tank walls or in the inevitable "sludge" on the floor of the tank. Gleaning operations lead to liberation of vapour; from the "scale" or "bludge".^* The toxic effects following absorption of tetra-ethyl lead are due to the lead content and are, fundamentally, precisely the same as those of poisoning with inorganic lead compounds. Absorption of tetra-ethyl lead into the circulation is somewhat;delayed in the lung and skin but after leaving the circulation it tends to reach relatively high concentrations in fatty tissues such ss t,,he brain, liver and subcutaneous fat. Subsequently the organic lead compound decomposes into inorganic salts which produce the - . K 0029055 - --- - -2-' toxic effects on the body cells, and especially the cells of the central . nervous system T'here there may- he a nigh lead concentration. Curing a period of 3 to 14 days after absorption the lead content, of the various tissues becomes redistributed so that its distribution is ultimately the K .5. : same as that following the absorption of inorganic lead compounds, fhe clinical features- of tetra-ethyl lead poisoning are characteristically those of an acute encephalopathy occurring after a 1,2,7. latent period which'will vary inversely with the degree-of exposure. Detailed descriptions have been given of the clinical features in articles . reviewing up to 78 cases of poisoning pM in this report? only brief ' reference will be made to the typical features. Within a few hours of exposure the subject develops increasing insomnia, weakness, restlessness, anorexia and tremors of his hands. If the exposure has been considerable there-may be Varying psychic changes, and, of these, excitement and mania re commonest. Wild and. terrifying dreams, hallucinations, disorientation, physical activity and convulsions mny herald an attack of scute mania. Other subjects may appear schizophrenic. Characteristically there is a, slow pulse rate, a normal or subnormal temperature, a lowblood pressure, little or no change in the m erythrocytes, and a tendency to diarrhoea rather than constipation. Colic mm may occur - but is not characteristic, general muscle pains are common bat neuritic phenomena are not seen. 2he condition is an acute lead encenhelonathV and the usual signs of chronic lead poisoning do not occur. ''.'ft ' , ' '' When severe symptoms become evident they do not disappear completely . ^ until recovery is ensiling - the general symptoms continue to progress and ; ; 2. there are no true remissions and relapses. It is stated that those cases K& 0020056 .UV .. -3' ; 1. with severe Ennis, requiring restraint, are "almost uniformly fatal*. Treatment has consisted of sdatxbn, fluids*, and maintainingthe urine alkaline to favour the excretion of lead or its deposition in bones. Hypertonic solutions:were often given to combat cerebral oedema. / 2:3"dimercaptopropanol, or BAL Anti-Levi was introduced 8. by Peters et al. as an effective antidote to Lewisite. bubsequent - investigations have shewn that BAL is an. effective antidote against poisoning 9 10 ;11. 12 1"?. 14,15l6. with arsenic,'"' ' mercury, ' * gold and bismuth. In vitro. it- will combine with iron, lead, tin, copper, cooalt, nickel, selenium, and ant irony, producing coloured and mostly insoluble compounds. BAL acts as an antidote to metallic poisons by forming stable compounds with the metals . by virtue of its own two thiol groups and thus preventing them from combining with essential thiol compounds in enzyme systems and so producing their toxic effects. The stability and Bon-dissoeL--bility of the BAL-setal , 8,17,18,19. compounds prevents tbera from being toxic. Two men, who were exposed to tetra-ethyl lead, and its derivatives, while they were cleaning out an aviation gasoline storage tank, developed typical signs of lead encephalopathy. One had mild sysrotoms but the other had convulsions, and became maniacal."- Both, were treated in Royal Prince Alfred Hospital, Sydney, with BAL and made complete recoveries. BAL was used for the treatment of these two men as it was considered possible that as lead is so closely related, chemically, to gold its toxic effects might similarly be counteracted. The possibility of BAL forming an insoluble compound with the lead in the tissues was considered but was thought to be of less importance than- the prevention of irreversible, changes KE 002005? -t" ' Jm -4- in the central nervous system. CASI HISTORIES. CASK I. R.K. a married storeman aged 30 years was admitted to Royal Prince Alfred Hospital at 12.30 a., on 23rd June. On the 19th Jtme he had commenced to clean out a storage ; petrol tank that had contained aviation spirit some 2 years previously hut recently had contained water. He proceeded to remove the "slime* from, the walls and internal `'fins* using a piece of timber, held in his ' ' '' ' '' bare hands# as a scraper and during this cleaning process he acquired a number of minor abrasions on both hands. Be wore rubber knee boots but ho respirator and though "the fumes were dreadfulH, he spent between 6 and 8 hours in the tank. Before eating his lunch he washed % %f his hands in soap and'water. J !, , On the morning of 2Qth June# having slept very poorly the : previous night, he felt tired, "off-colour" and hsd some anorexia, but continued to clean the tank. He spent half the working day, wearing -,^ neither gloves nor respirator, on the floor of the tank scooping up .SC the sludge with a tin and then pouring it into a bucket. One man filled the bucket on the floor of the.tank while the other hauled up the full bucket and disposed of the contained sludge. Bach 10-20 minutes' J it the two men would change their Jobs, as the-"fames in the tank were so baa"^ He slept very little that night and had terrifying dreams, his appetite was ncn-existent, and he felt ill. ". &*4 %?} S 0 |1S1 On 2lst June he "felt awful", had diarrhoea* marked nausea,Sand some epigastric pains. He was weak and noticed an aching pain in his . - 5- upper and lower jaws. He was admitted lb the local hospital with a diagnosis of a gastro-intestiaal unset which was very prevalent in the town at the time. After admission his intestinal symptoms settled down and.. ... i;- . ' . 'M within a day his diarrhoea had ceased, but he still had marked anorexia. ' ' i '' ' He noticed a peculiar sensation in his hands he continually wanted . - to rub them together. On the morning of 2<aid June he was a little - confused and in the early afternoon, had a clonic fit during which .'Vh he was unconscious. Recovering from his fit he was sore confused and very restless. He was sent by ambulance to Royal Prince Alfred Hospital where-on* admission he eoul not clearly recollect the above detailed events. There were no relevant facts elicited in his past or personal ; history. . On Examination: He was a young man who writhed on the bed making curious stretching movements of his limbs and back and continuously rubbing his hnnds over his face. He seemed to be little interested in his surroundings. He tongue was dry and coated and his skin warm, dry and of normal colour. There were a number of superficial abrasions on the backs of both hands. >lk complained of pains all over his abdomen but there was no local tenderness. There was some tremor of his extended hands. His radial pulse was of good volume, regular and its rate was 64 per min; his arterial blood pressure was 120/55 n of mercury, and his oral temperature 98.4P. His eyelids were widely separated so that he appeared to be exophthalmic but his pupils were' central, circular and not dilated. Ho other abnormalities wer/found oh physical examihation. H|s weight was 150 lbs. Treatment and Progress: He was confined'to bed and given sodium phenobarbitone and morphine sulphate. He was given 750 1 saline with 5$ glucose and 50 ml. sodium lactate solution intravenously. Subsequently sodium citrate was given orally, in sufficient quantity to keep his urine neutral or alkaline to litmus. He received calcium lactate 10 grains three times a. day and had been given parenteral calcium gluconate by his local practitioner before being sent to Sydney. Treatment with 3-\L (a lQjfe solution of 3-dimercaptopropanol in peanut oil with 10$ benzyl ben so ate) was commenced at 2.30 a.m. 'when 4.4 mg/kg (1 ml. per 50 lbs) were given by intramuscular injection into his buttock. Subsequently 4*4 mg/kg were injected each"four hours for 3 doses, then 2.2. mg/kg were given twice daily from 23rd June to 27th June. His only reaction to SAL was that he said the smell put him off his food. On the morning of the" 27rd June he still appeared; to be exophthalmic; his tongue was dean and he was db'pey% but by mid-day he had greatly improved. He was then much clearer mentally end was taking some food as well as fluids by mouth. He stated that his jaws were still sore and that Ms muscle pains, though present, were . less severe. He felt tired but was unable to sleep without sedatives. On the following day he looked better, but had cramps in his calves which were a little tender, and be was very restless and active :` in bed * He was refusing all food; for he said it tasted of BAl. His eyes were wdry and sore8. He had no diarrhoea or vomiting. Statins: the next' two Says his* condition -generally improved,' and he began to eat more food. Ke had, some headache, was still excessively alert, Ms pupils were dilated, 'and he appeared to be exophthalmic. Considerable difficulty x?aa experienced in inducing sleep* He complained of some local pain following his BAL injections ` and vomited once. On the 27th June he was very restless and mentally active in the early morning, but towards mid-day became unstable, refused treatment and commenced walking around in the ward. At 12.15 p.m. he became hypopmanie and escaped into the street for a few minutes. Be was returned, with.-persuasion* to the ward and given morphine sulphate, hyoseine hydrobibfiide -and BAL 4.4 mg/3g at 1.10 p.m. His mental condition was confused, excited and deluded. At I.30 P.m. he had an epileptiform fit with typical clonic and tonic phases and involuntary micturition. Following his ,!fitH he was hallucinated, disorientated and tended to become violent. .,v : He tore up his pyjamas and frustrated an attempt to give him hypertonic . glucose intravenously after Some 250 s:&. had been given.- In spite of - large doses of hyoseine hydrobromide. Dial and sodium phenobarbitone his psychomotor activity was little abated though he was less violent. At 7.30 p.m. he passed urine into his ,bed. BAIi was given in 4.4 mg/kg doses at 1.10 p.m. , 4.30 P*33* snd 8.50 p.m. but he as very restless and confused and was only partly controlled with four hourly hyoseine hydro bromide . On the 28th. June he contihued to be hallucinated, deluded and disorientated. He was quite irrational - laughing and talking to -1 - - 8 - himself whilst prowling round the room, and was most uncooperative* He was somewhat quietened with Hembutal and slept during the later part of the night. BAL in doses of 4*4 mg/hg was given at 2, 3D ; and 6.3O a.m. and 3*2 g/kg at 8.30 p.m. By the next day he had greatly improved - he could talk rationally for brief periods, was more cooperative and, assisted Fembut&l, slept most of the day. He received BA1 4.4 mg/kg at b am* and 6 p.m. each day until 3rd July. On 30th June he was very much improved, was quiet all day, and only required sedation at night. .. -sm. Between 29th June and Jrd July his mental condition improve!! I and was normal except for insomnia, unpleasant dreams which were '- still very troublesome, and restlessness. He felt Hdopeytt most -f 'Jt of the time on account of the Femhutal he was receiving. . He. increasingly complained of muscle pains which made hi want to s-bretjh. .. . - -h continuously, hut by 3r& July, these movements caused so much pain ,, ;- . ,, .. - ; that he could only sit up with considerable difficulty. During: time he had some abdominal colic with frequent bowel actions (approximately three per day). On 3rd July his tongue was dry and dirty and he did not so well. He was given BAL 4.4 g/kg fourth hourly beginning aft 6 p.m. By 4th July he felt better and he could obviotisly move with much less discomfort and his abdominal pains had abated. His discs and, fundi were normal. BAD 4*4 g/hg fourth hourly was ^ 00,20,; 62 ) CO <} O O CM o o w continued till 10.50 p.. *hsa in error, he received .a dose of 8.8 ag/kg./- He developed a marked reaction with, parasthesiae of his limbs, face and mouth; he was giddy* prostrated and dyspnoeic, and had a constrictive pain in his chest. His arterial blood pressure rose to 190/13O ees of mercury. These symptoms were transient and by the next morning he was feeling much improved over his condition of the previous morning - his muscle pains were less, he felt better and he had less abdominal discomfort. All the symptoms that had occurred the previous night had vanished. From the 5th to 14th July his progress was steady and only interrupted by the development of a mild infection in one buttock which rapidly responded to Sulphadiazine. On the Jth July he developed a rash which was erythematous and macular on the arin and legs, but finely papular on the palms and soles. All his pains vanished, he became mentally quite normal, and he required diminishing amounts of sedation each night. After 10th July he had nausea^ often With vomiting,. after each injection . of 'B'AL.;vn:_^ . ;; jV` .' ' from 5th to 13th July he received 2.9 mg/kg BAL eight hourly and from 14th to 2lst July 1.5 g/kg twice a day. Blood pressure readings were usually between 150-200/100-110 j o b of mercury depending on how recently BAL had been given, but by the :14th July his blood pressure was 125/60 mm of mercury. His pulse rate ranged between 48 and 66 per minute during the first five days in hospital, during the next week between 60 and 75 per minute. Jf ":,'4 4"', -:i - 10 . * " -4 : . and after 5th July between JO and 90 per minute. . " '4 -:A ' ' J His oral temperature varied between 9^.8f and $8.4^ during the first ten r, [ ? r days after admission but the. majority.of readings were below 90OF. r . Until the 28th July his sleep was always interrupted by dreams which gradually lost their unpleasant character and on 4, discharge from hospital on JOth July he was sleeping and dreaming ^ normally. His rash disappeared rapidly after ceasing BAL administration. Laboratory Bata. /' 1. Daily excretion of lead in the urine: ' .. 1 f w ' 7f| - *< Date Dumber of days since Urine lead content Urine volume4 first, expo sure to lead (m/t per 24 hours) (mils ner 24 honrt 54/6 58/6 2/7 4/7 5/7 6/7 111 9/7 4 5 9 13 15 16 17 18 20. 0.00 O.JO 0,11 0.13 0.12 0.08 0.03 O.O3 trace 37 (admission - . 4 specimen) e* (incomplete) 2500 -. 2380 - 2400 '>' 4rli Blood Counts: 23/6 ' Haemoglobin concentration 14.5 grasme per 100 ml.; very occasional stippled red blood cell seen; total'/ leucocytes 14*100 per c.mm. of which 8l% were 4 neutrophil granulocytes. 9/7 . - Haemoglobin - concentration 13*7 .gramme per 100 ml.; no stippled red blood cells seen; total leucocytes 7ft>0 per c.ram* of which 77% were neutrophil ; granulocytes. 4' . '. 0020064 >&\i :,.5~ i ; - 11 - r-, . `y-y's CASES II. : ' . - ' . , 7 =:;y f.J. , aged 34* & married storeman-driver with 3 two children, was admitted to Hoyal Prince Alfred Hospital at IO.3O P*tv on 2?nd done. . . >y y On 20th June he had assisted R.K. in the collection and disposal of the sludge on the floor of the tank already described* He wore protective rubber knee boots, canvas gloves, bat no ;\ respirator was worn. He also noticed that the ''fuses*' were very1 bad inside the tank. ` ;% . . \_.y -y ;r\ V.f He developed sarked insomnia, anorexia, and a 8 sickly feeling y in the stomach1* on the evening of 2oth dune and these symntoras had ' . . - 't'yl increased until his admission to hospital. He had mild diarrhoea for a-"few^dayet- which had. ceased, on arrival in Sydney*.1 On admission he felt very tired but apart from slight headache tremor of his hands, which had been, present, for one day, he bad no other .symptoms, y^Sy/C , He attributed his initial gastro-intestinal symptoms to flfood-poisoning8 , which was prevalent at this time in the Hotel in which he was staying, but the development of insomnia and tremors with marked anorexia censed him to consult a doctor, :.yv-y Heither his past nor Ms personal history revealed any relevant facts. /' .4 On Examination; He was a rather worried, ruddy-faced, red-haired young man. His skin was warm'and dry, his pupils appeared to be somewhat dilated but were otherwise normal, and r; apart from evidence of lat^; of sleep he appeared Jwell. He had a moderate tremor of both hands. His arterial blood pressure was . KZ 0020063.' I;* M 120/75 cm of mercury, , pulse rate 66 per tain, and his oral* temperature $S~F. There were no other abnormal physicalsigns. His weight was 1?5 lfcs? Treatment end Progress; He was confined to bed end given barbitone sedation. His -urine was kept neutral or alkaline' V- . in reaction by oral potassium citrate; sufficient fluids were administered to keep his urine volume up to or over 2 litres ppr diem, ' - % and calcium lactate was given by south. ; 3AL (10$ 2; 3-dimer captopropanol in peanut oil with 10$ benzyl benzoate) was given intramuscularly into the buttocks each four hours, commencing at 12.15 a.zrt. on ?3r& June, for four doses which were 4.4v^s/^g 3*5^g/^g 4.4,.g/kg and 3.5 mg/kg respectively. following the first injection there was a moderate reaction - he shivered, felt giddy and then sweated; he felt nauseated, had some muscle pains, and he had pain in his abdomen and at the site of the injection. Eeactions characterised by nausea and vomiting, and usually with pains in his ears accompanied the next three injections of BAL - in each instance cosing on some 15-3P minutes after the ' -Kinjection.v : . H- ** V - , On the day following admission his anorexia diminished and he began to eat well. At 9,30. p.m. on this day he had 2.2 mg/kg of BAL injected into his buttock and this dose was subsequently given at 9.30 each morning and evening during the next four days. He continued to -* have pain in his buttock and ears following each injection. KE" 0020068 A In the evening of the 25th June he became very "bright*' and complained of some headache. As his restlessness, which had been present since admission was increasing, he was given mornhine sulphate in the evening. He had not slept well since admission in spite of barbitone sedation, and it had been noticed that his palne'bral fissures were widened so that he appeared exophthalmic. His pupils were considerably dilated during this period. On the morning and afternoon of the 27th he became very restless and upset about his friend (Case l), and for a while he was most uncooperative. However, he responded to increased sedation with phenobarbitone and slept well, As he was rather restless and unMllihg to stay in bed during the following three days he was kept heavily sedated with phenobarbitone. BAL 3.9 mg/kg was given 6 hourly on 28th June, 1.9 g/kg 6 hourly on 29th June and from 30th June to 3rd July 3.9 mg/kg was given twice daily. From the 30th June onwards his improvement was continuous; his eyes became normal and lost their exophthalmic appearance, his ^ pupils contracted, he became-a quiet and most amenable man, and, apart from a minor infection in the left buttock (rapidly cured with Sulphadiaeine) he made an uninterrupted recovery. - Hie dosage, of SAL was reduced to 1.9 mg/kg twice daily on 4th July and to 1,9 mg/kg daily on 11th July; he received his last dose on 14th July Bis arterial blood pressure was 12q /75 mm of mercury on 29th June and 140/80 mm of mercury on 14th July. His fundi were reported to be normal on 4th July. .During the first five days after admission his pulse rate ,w . KE 0020067;.,;.. ^JfSI kil 1 `-tl ranged between $2 and Go per minute with but three readings over 60; =- his oral temperature ranged between 97 sad 98F for the most part. Laboratory findings: :|"1w|: 1. Daily excretion of lead in the urine: . . fi . 'Ilf: Date, Days since exposure Content of lead, in Urine 4 tag, per 24. hours.volume in milt 24th dune 26th June 27-28th June 28-29th June 30-1st July 2-3rd July 4<-5^h July 5-6th July . 7-7th July 4 6 8 9 11 13 15 16 17 O.09 0.09 0.79 0.50 0.45 0.24 0.03 trace trace 3640 4340 3450 1050 Blood Counts: 23rd June Bed blood cells 5*67 million per c.ram.; haemoglobin Concentration 17.2 gramme per 100 ml.; total leucocytes 11,000 per c.ratn., neutrophil granulocytes 9C$. U0 stippled' cells were seen. DISCUS5101?. fromThere is no question that both these sen were suffering the ofeffects tetfa-ethyl lead absorption* and that the route of absorption was both the ltaxgs and the skin#Though both nen had changing amounts of s*t tolead in their urine specimens it was interesting note that sore fromlead was found in the urine from T. J. (Case II) than 3b the urine B.I. (Case I) who was more seriously affected and had such greater exposure. The excretion of lead in the urine is variable, and, in the experimental animal and man, there is usually more excreted by the bowel than by the 12 20 21 kidney after the absorption oftetra-ethyl lead. ' ' ' ' It is also Kg-: 0020068 possible that therapy with BAL effects the amount of lead recovered from urine as either the compound of 3Ah and lead may he relatively insoluble and .' 22 therefore, not apprecially excreted, or the method used for the estimation of the lead content in the urine may not be adequate for the detection of BAIt-laadtcompounds. In view of the limitations of the adsorption method of estimating lead in the urine and considering that B,&. (Case I) received much larger doses of 3Ab than did ;T.J. (Case II) it. seems more likely that the amounts of lead recovered were not true indications of the amounts actually present and that the BAL-lead compound was not recovered completely by this method. The intoxication in T.J. (Case II) was relatively mild when compared with that of K.K, (Case I) who was seriously ill following much greater exposure. As the clinical features of the two men were parallel the discussion will largely centre round the more seriously affected man. fhe clinical features of both men were typically those-.following the absorption of tetra-ethyl lead. In E.K. (Case I) minor symptoms appeared a few hours after exposure but within 48 hours serious symptoms were present - the early development of confusion, restlessness and of an epileptiform attack indicated massive absorption of tetra-ethyl lead* - B.K.'s illness was atypical in that his severe symptoms almost completely remitted, after some l6 hours of treatment, for 4 days during which he felt well. These symptoms returned with increased severity and he became maniacal, tried to escape and had another epileptiform attack. These severe symptoms remitted after 2 days of treatment but he remained well for only 4 days before symptoms were again remarked. On this occasion his symptoms were not related to the central nervous system but to his w^sr'^ Ke 0020069 JUr UTS- J - 16 - general musculature sad abdomen. Such definite remissions of severe symptoms do not characteristically occur in subjects with tetre-ethyl lead poisoning. .' Both of the remissions mentioned above and the final abolition of the last recrudescence closely followed the administration of large dosec of 3AL. Furthermore, each recurrence followed within 4 days of the redactfc of the dose of BAL to a maintenance level. The patient himself was most insistent that BAL relieved his muscle pains and abdominal discomfort ia bis last recrudescence. It is suggested that the course of the intoxication in E.E. (Cag# j)- was as follows: tetra-ethyl lead, absorbed from the lungs and skin, bepjtsa relatively concentrated in the central nervous system and, when the .orj$gg^' covTound broke down, to inorganic lead salts, symptoms were produced.? o^.-'lte. administration -of BAL a non-toxic compound was formed which was, perhaps;,, relatively insoluble; with reduction of the dose of BIB either some of non-toxic BAIi-lesS. compound, was broken up freeing inornate lead* o-r else tetra-ethyl lead still prelent in the organic state conMnuei, to he assmveriejS to toxic inorganic lead; in either or bo th instances /there were isad<eu|$e amounts of BAL present to render the lead non-toxic and symptoms 3S&&& .OHfirfxtf further administration of large doses of BAL again had a fall antidote but reduction in dosage once care resulted in the recurrence of sympt^atf^f these last symptoms were probably due to lead distriouted throughout' organism as sufficient time had now elapsed for this to ocrass once 2 O.02O070V ' 'jit - : .v.. y adequate dosage of BAB haft a full antidotal effect. It is difficult to atbvlft the conclusion that BAB was the active agent in the production of remissions, especially as other therapy did not change apart from some variation in the dosage of sedatives. A large amount of BAIi was given to R.K. (Case I) who received some lS grammes in all. It is considered, nevertheless, that larger doses should have been given for a longer period of time in the early stages of his intoxication. It has been reported that for the relief of encephalopathy from tnercay poisoning far higher doses are required than for other forms of mercury intoxication and a similar set of circumstances may prevail in lead intoxication. It seems important to stress the apparent need for continued high doses of BAB in acute lead encephalopathy - smaller doses may lead to failure and, it is possible,.to ill effects. Some arsenical compounds when combined with 1 mol of BAB have been found to be more toxic than the original arsenical . ?3. compound, though cols of BAB render them non-toxic. It appears that full doses of BAB (4.4 mg/kg) should be given each 4 hours till all symptoms have subsided and then doses of 4*4 rag/fcg given three times a day for another 14 days before ceasing it3 administration. Treatment should be instituted immediately exposure to toxic concentrations of tetra-ethyl lead has taken place;.. , vlv,- ; Toxic effects from BAB occurred in both ben, mildy in T.J. snd limited to some local pain at the site of injection and an earache following each injection of 4*4 mg/kg. R.K. (Case I), on the other hand, shewed both acute and chronic toxicity. On the evening of the I?;th day of treatment he receives; in error;. 8.8 mg/kg in one dose and. rapidly developed prostration *; - iB -. V; ' a constrictive feeling in his chest, dyspnoea, limb and oral parseathesiae, and a feeling that "he had no nose". His blood pressure rose to I90/I3O nrn of mercury at this time. These symptoms were transient and had all cleared by the next day when he felt much improved. On the, 15th day of BAL - administration he developed a typical drug rash - he had a Btacttlo-erytheiaatotis rash on his forearms, arms, thighs and legs which was mainly on the dorsal surfaces and a papular rash on both palms and soles. Itching was Quite marked. The rash rapidly disappeared on cessation of BAL injections. SPHMARY. 1. Two men suffering from tetra-ethyl lead poisoning have been reported. 2. Beth men were treated with 2:3-dimercaptopropan0l (BAL or British Anti-Lewisite) and made full recoveries. 3. Continued high dosage of 2*3-dimercaptopropanol (44 mg/kg . administered as a 10ft solution in peanut oil with 10$ benzyl benzoate intramuscularly each 4 hours) was necessary to produce a complete antidotal effect. 4* * Acute and chronic toxic phenomena followed the administration of the 2:3-dimercaptoprop3nol solution in both men but were not serious in either. My thanks are due to Dr. l.M.A. Bay, Biochemist in the Fairfax Institute of Pathology, Royal Prince Alfred Hospital, for the estimations of the concentration of lead in the urine specimens. KE 0020072 k MbSfc" i V -. - 19 BKEggBIKSBB. *1T ! ' . 1 1. Kehoe, R.A.: Teira-ethyl Lend Poisoning. Clinical Analysis of a scries of Ron-Fatal Cases. J.A.M.A. 85*1QS 1925. :4 >>* .2 Sachle, W.F.: Tetra-ethyl Lead Intoxication and Poisoning by 1 delated Compounds of Lead. J.A.M.A. 105:578* 1935* "- ? d 3- Keboe, H.a ., Thamann, F., and Cholak, J.* An Appraisal of the Lead \ \ Hazards Associated, with the Mstribution and Use of Gasoline * Containing Tetra-Ethyl Lead II The Occupational Lead Exposure of Filling Station Attendants and Garage Mechanics. J. Indust. ; . Hyg. & Toxicol. 18*42, 1936. ' I *1?4* The Associated Ethyl Company Ltd., London. . . Information concerning the Properties, Handling and Mixing of Ethyl Fluid. 1939.' ** 5. Kehoe, S.A. and Thamann, Fit The 3ehaviour of Lead in the Animal Organism. II Tetra-ethyl Lead. to. J. Hyg. 15*478, 1931* 6. Kehoe, fi.A. * On the Toxicity of Tetra-ethyl Lead and Inorganic Lead Salts. J. Lab. fc Clin. Med. 12*554, 1927, 7. Cassells, B.A.K. & Hodds, E.C.: Tetra-Ethyl Lead Poisoning. B.M.J. . ii:68l, .1946. "8. 9. .10 ll. Peters, R.A. Stocken, L.A., and Thompson, H.H.S. * British AntiLewisite (BAL) Mature 156*616, 1945* . 'I- b - :-5:;-'j.y; \ by, . . ^W-y W ' , . . Carle ton, A.B., Peters, R. A. Stocken, L.A,., Thompson, S. H. S., and ** * Williams,-Dil. * The Treatment of Complications of Arsenotherapy - with BAL. J.: Clin. Inv. 25i497, 1546. ' ' *, ' \ r /,- Regie, H., Magnuson, H.J., and Fleishman, R. * The Systemic Treatment . ` of Experimental Arsenic Poisoning (Mapharsan, Lewisite, Phenyl Arsenoxide) with BAL J. Clin. Inv. 25*451, 1946. '` : ................. ; x" ~ Longcope, W.T., Leutscher, J.A., Wintrobe, M.K., ana Jager, F.s The Treatment of Arsenical bpsneat it is with Preparations of'BAL. J. Clin. Inv. 25*528, 1946. ' is. Gilman, A., Allen,. R.P., Phillips, F.S., and St. John, E.: The ..^Treatment:of .Acute Systemic Mercury poisoning in Experimental Animals with BAL, Thiosorbitol 1, and BAL glucoside, J. Clin. , . Inv. 25*549. 1946. ' *+*!* * * f : KE' 0020073 t A/ 'te-`rwsT^.s, i 13* Longcope, W.T., Leutseher, J.A. j The Treatment of Acute Mercury Poisoning by BAL J. Clin, Inv. 5:557, 1946. 14. Regan, C., Boots, B.H., Grechin, A.F.: She Treatment of Gol4 r Derraatitides, Use of Bal {2:3-diinercnptonropanol) . J.A.M.A, -u 133:752. 1947. 15. Lockie,,L.H., Foreross* B.U., & George, C.F. r Treatment of Two reactions to Gold.. Response of Throrabopenic Purpura and' granulocytopenia to BAL therapy. J.A.M.A. ' 133:754* 1947* 16. Cohen, A. & Goldman, J.: The Treatment of Acute Gold and Arsenic Poisoning. Use of BAL (2:3~dimercaptopropanol, British Anti-Lewisite) J.A.M.A. .133*749* 1947* 17* B'arro'ni,i':E.S,G.t. Miller-," 2.B'., Bartlett, G.H,, Meyer, J. & Singer T.F Reactivation by Bithiols of Enzymes Inhibited by Lewisite. Biochera J. 41:69, 1947. ' r!R:? .*, : 18. ...Webb,- B.C., & Van Heyningen, B.: The action of British Anti-Lewisite (BAL) on Enzyme/Systems Biochera J. 41:74* 1947. 19. Stocken, L.A., Thompson, R.H.S., & Tfhittaker, V.p.: 3ritish-Ant.i- Lewisite 4 Antidotal Effects Against Therapeutic Arsenicals Biochera J. 41:47* 1947* . 20. Kehoe, B. A. :Lead Absorption and. Lead Poisoning. Med. Clin. F. America 1942 (July). 21. - Kehoe, A., Cholak, J., Hubbard, B.M., Barabach, K., KcUary, B.R., & Story, B.?.s Esperiraent&l Studies on the Ingestion of Lead Compounds. J. Indust. Hyg. & Toxicol 22:581, 1940. 2?. Psnhall, L.T.: A Rapid Method of Analysing Urine for Lead. - Lead Studies XI. J. Biol. Chera. 60:485, 1924. 23. Peters, R.A. & Stocken, L.A.: Preparation and pharssacological -Properties of 4-hydroxy rsethyl-2-(3-aaim-4'-h3^.roxyphenyl)-l 3-dithia-2-arsacyclopentane (Marjiiarside-BAL compound). Biochera J. 41:53* 1947* , KZ 0020074 .